Implication de la voie de signalisation des rétinoïdes dans la mémoire relationnelle et ses dysfonctionnements

Les rétinoïdes (métabolite de la vitamine A), en régulant l'expression de nombreux gènes codant pour des protéines neuronales spécifiques, interviendraient dans les processus de plasticité synaptique supposés soustendre l'élaboration et la conservation de représentations mnésiques/relationnelles. Cette hypothèse a été éprouvée en utilisant deux modèles physiologiques d'hypofonctionnement de ce signal nucléaire (vieillissement et jeune adulte en carence vitaminique A). La première partie de ce travail a consisté à valider, dans un labyrinthe radial deux protocoles expérimentaux visant à évaluer de façon sélective chez la souris les processus de mémoire relationnelle et ses dysfonctionnements au cours du vieillissement. Ces deux épreuves comportent chacune deux étapes. L'animal doit d'abord apprendre la valence respective (présence ou non d'un renforcement alimentaire) de 6 bras du labyrinthe. Cet objectif atteint, la deuxième étape vise à modifier le mode de présentation de ces informations. Dans l'ensemble, nos résultats montrent que seules les performances en situation de choix (discriminations simultanées de 2 bras) sont affectées par le vieillissement, qui à l'inverse n'altère pas les performances en discriminations successives (présentation des bras l'un après l'autre). Nous avons mis en évidence chez l'animal hippocamptomisé le même type de déficit. Dans la deuxième partie de notre travail, nous montrons 1°) sur le modèle du vieillissement, que la restauration du signal nucléaire contrôlé par les rétinoïdes à un niveau normal d'expression (par un apport exogène d'acide rétinoïque) s'accompagne d'une suppression du déficit mnésique (relationnel) associé 2°) que l'animal jeune carencé en vitamine A (diminution du signal comparable à celle observé chez l'animal âgé) présente le même déficit cognitif que celui observé au cours du vieillissement. Ces résultats suggèrent une relation fonctionnelle entre la voie de signalisation des rétinoïdes et la fonction mnésique.Retinoids, (derivatives of vitamin A) regulate gene expression via their nuclear receptors. They have been implicated in the synaptic plasticity of the hippocampus and might therefore play some role in cognitive functions. We have directly investigated this hypothesis by using two mouse models of retinoid hyposignalling (ageing and vitamin A deficiency in young mice). We first developed a mouse model of the age-related declarative / relational memory deficit. This consisted of using two-stage paradigms comprising an initial learning phase followed by a test phase in an 8-arm radial maze. We showed that aged mice were able to discriminate normally between three always-rewarded and three never-rewarded arms when they were presented one at a time; conversely they failed in two-choice discrimination trials calling for judgement of the relative valence of the two arms. In another series of experiments, this same type of selective memory deficit was observed in hippocampal-lesioned mice. In the second part of our study, we showed that 1) administration of retinoic acid to aged mice normalised the level of retinoid signalling in the brain and at the same time completely alleviated their relational memory deficit. The beneficial effect of RA on memory performance was abolished by co-administration of a RAR antagonist. 2) vitamin A deprivation in young mice resulted in a reduction in the level of retinoid signalling (similar amplitude as that seen in aged mice) and induced a selective relational memory impairment similar to that observed in aged mice. The results suggest the existence of a functional relationship between retinoid signalling in the brain and cognitive functions

The brain-derived neurotrophic factor Val66Met polymorphism is associated with reduced functional magnetic resonance imaging activity in the hippocampus and increased use of caudate nucleus-dependent strategies in a human virtual navigation task

Multiple memory systems are involved in parallel processing of spatial information during navigation. A series of studies have distinguished between hippocampus-dependent ‘spatial’ navigation, which relies on knowledge of the relationship between landmarks in one’s environment to build a cognitive map, and habit-based ‘response’ learning, which requires the memorization of a series of actions and is mediated by the caudate nucleus. Studies have demonstrated that people spontaneously use one of these two alternative navigational strategies with almost equal frequency to solve a given navigation task, and that strategy correlates with functional magnetic resonance imaging (fMRI) activity and grey matter density. Although there is evidence for experience modulating grey matter in the hippocampus, genetic contributions may also play an important role in the hippocampus and caudate nucleus. Recently, the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene has emerged as a possible inhibitor of hippocampal function. We have investigated the role of the BDNF Val66Met polymorphism on virtual navigation behaviour and brain activation during an fMRI navigation task. Our results demonstrate a genetic contribution to spontaneous strategies, where ‘Met’ carriers use a response strategy more frequently than individuals homozygous for the ‘Val’ allele. Additionally, we found increased hippocampal activation in the Val group relative to the Met group during performance of a virtual navigation task. Our results support the idea that the BDNF gene with the Val66Met polymorphism is a novel candidate gene involved in determining spontaneous strategies during navigation behaviour

Retinoic Acid Restores Adult Hippocampal Neurogenesis and Reverses Spatial Memory Deficit in Vitamin A Deprived Rats

A dysfunction of retinoid hippocampal signaling pathway has been involved in the appearance of affective and cognitive disorders. However, the underlying neurobiological mechanisms remain unknown. Hippocampal granule neurons are generated throughout life and are involved in emotion and memory. Here, we investigated the effects of vitamin A deficiency (VAD) on neurogenesis and memory and the ability of retinoic acid (RA) treatment to prevent VAD-induced impairments. Adult retinoid-deficient rats were generated by a vitamin A-free diet from weaning in order to allow a normal development. The effects of VAD and/or RA administration were examined on hippocampal neurogenesis, retinoid target genes such as neurotrophin receptors and spatial reference memory measured in the water maze. Long-term VAD decreased neurogenesis and led to memory deficits. More importantly, these effects were reversed by 4 weeks of RA treatment. These beneficial effects may be in part related to an up-regulation of retinoid-mediated molecular events, such as the expression of the neurotrophin receptor TrkA. We have demonstrated for the first time that the effect of vitamin A deficient diet on the level of hippoccampal neurogenesis is reversible and that RA treatment is important for the maintenance of the hippocampal plasticity and function

Expression of the retinoic acid catabolic enzyme CYP26B1 in the human brain to maintain signaling homeostasis

Date of Acceptance: 27/08/2015 Funding was provided by the Wellcome Trust grant WT081633MA-NCE and Biological Sciences Research Council Grant BB/K001043/1. Prof Fragoso is the recipient of a Post Doctoral Science without Borders grant from the Brazilian National Council for Scientific and Technological Development (CNPq, 237450/2012-7).Peer reviewedPublisher PD

Fish, docosahexaenoic acid and Alzheimer’s disease

Cognitive decline in the elderly, particularly Alzheimer’s disease (AD), is a major socio-economic and healthcare concern. We review here the literature on one specific aspect of diet affecting AD, that of the ω3 fatty acids, particularly the brain’s principle ω3 fatty acid – docosahexaenoic acid (DHA). DHA has deservedly received wide attention as a nutrient supporting both optimal brain development and for cardiovascular health. Our aim here is to critically assess the quality of the present literature as well as the potential of ω3 fatty acids to treat or delay the onset of AD. We start with a brief description of cognitive decline in the elderly, followed by an overview of well recognized biological functions of DHA. We then turn to epidemiological studies, which are largely supportive of protective effects of fish and DHA against risk of AD. However, biological studies, including blood and brain DHA analyses need careful interpretation and further investigation, without which the success of clinical trials with DHA may continue to struggle. We draw attention to some of the methodological issues that need resolution as well as an emerging mechanism that may explain how DHA could be linked to protecting brain function in the elderly

Implication de la voie de signalisation des retinoïdes dans la mémoire relationnelle et ses dysfonctionnements

Les rétinoïdes (métabolite de la vitamine A), en régulant l'expression de nombreux gènes codant pour des protéines neuronales spécifiques, interviendraient dans les processus de plasticité synaptique supposés sous-tendre l'élaboration et la conservation de représentations mnésiques /relationnelles. Cette hypothèse a été éprouvée en utilisant deux modèles physiologiques d'hypofonctionnement de ce signal nucléaire (vieillissement et jeune adulte en carence vitaminique A). La première partie de ce travail a consisté à valider, dans un labyrinthe radial deux protocoles expérimentaux visant à évaluer de façon sélective chez la souris les processus de mémoire relationnelle et ses dysfonctionnements au cours du vieillissement. Ces deux épreuves comportent chacune deux étapes. L'animal doit d'abord apprendre la valence respective (présence ou non d'un renforcement alimentaire) de 6 bras du labyrinthe. Cet objectif atteint, la deuxième étape vise à modifier le mode de présentation de ces informations. Dans l'ensemble, nos résultats montrent que seules les performances en situation de choix (discriminations simultanées de 2 bras) sont affectées par le vieillissement, qui à l'inverse n'altère pas les performances en discriminations successives (présentation des bras l'un après l'autre). Nous avons mis en évidence chez l'animal hippocamptomisé le même type de déficit. Dans la deuxième partie de notre travail, nous montrons 1ʿ) sur le modèle du vieillissement, que la .restauration du signal nucléaire contrôlé par les rétinoïdes à un niveau normal d'expression (par un apport exogène d'acide rétinoïque) s'accompagne d'une suppression du déficit mnésique (relationnel) associé 2ʿ) que l'animal jeune carencé en vitamine A (diminution du signal comparable à celle observé chez l'animal âgé) présente le même déficit cognitif que celui observé au cours du vieillissement. Ces résultats suggèrent une relation fonctionnelle entre la voie de signalisation des rétinoïdes et la fonction mnésique.BORDEAUX1-BU Sciences-Talence (335222101) / SudocSudocFranceF

The impact of the affinity on ASD people visual engagement

International audienceAutism spectrum disorders affect the way people perceive their environment and interact with it. Many autistic people have a passion for an object or a topic, such as a film, planes, or geography maps to name very few of them, which is called an affinity. This affinity is sometimes described as an obsession that prevents the ASD subjects to connect with the surrounding world, but it is also considered as a key to the autistic world and a way to make a connection. In this paper we investigate the specific role of affinity in the autistic person’s attention. We have conducted eye tracking experiments over 44 autistic subjects from 3 different institutions. We have shown them neutral images and images with their own affinity and recorded their gaze position. Results are not conclusive in all the 3 institutions, but in the 2 first ones we got significant differences between the 2 sets of images indicating a higher visual attention for the affinity

Does personal interests affect visual attention? - An eye tracking study

International audienceEye tracking technologies have shown during the last decade a huge increase in performances, and hence in application fields. Especially in psychology and neuro-development, it is frequently used because of its non invasivity and its ability to give insights about mental processes. In this paper, we investigate the impact of personal interests on our visual attention. The question of attention is very important because of its link with memory and learning. Our results show that the gaze behavior when faced with neutral stimuli or others representing personal interests is the same for adults participants. However, when we consider children, slight differences appear in favor of increased attention